Our goal is to develop a potent adjuvant that can strongly, but safely, boost the immunogenicity of cancer vaccines. The proposal is based on recent observations that IL-2 and GM-CSF can individually increase the immunogenicity of vaccines, and that the adjuvant activity of each cytokine is markedly increased by co-encapsulating the cytokine into liposomes together with the vaccine. As each cytokine upregulates vaccine immunogenicity by different mechanisms, the combination of both cytokines should result in a particularly potent adjuvant. To test this hypothesis, we propose to conduct a randomized phase II trial to examine: 1) Whether IL-2+GM-CSF co-encapsulated into liposomes together with a melanoma vaccine can increase vaccine-induced cellular immune responses more strongly than either cytokine alone. Patients with resected AJCC stage III melanoma who are HLA-A2(+) will be randomized to treatment with a polyvalent, shed melanoma antigen vaccine encapsulated into lipsomes together with IL-2 or GM-CSF, or with both cytokines. The magnitude of vaccine-induced CD8+ T cell responses to A-2 restricted peptides derived from MAGE-3, MART-1, gp100, tyrosinase and TRP-2 will be measured by ELISPOT at baseline and at fixed intervals following immunization. 2) Whether IL-2+ GM-CSF lipisomes can enhance vaccine-induced antibody responses more strongly than either cytokine alone: Vaccine-induced antibody responses in the 3 groups of patients will be measured to individual melanoma antigens by Western immunoblotting. 3)The safety of this treatment/ Side effects will be followed by standard procedures. Major strengths of this proposal are that we have already demonstrated that IL-2 liposomes and GM-CSF liposomes are individually potent vaccine adjuvants in humans, that we have determined the optimal doses of each cytokine that maximally enhance vaccine-induced immune responses when encapsulated into lipsomes, that we have developed assays that are sufficiently sensitive to measure vaccine-induced CD8+ T cell and antibody responses to individual melanoma antigens, and that the vaccine contains multiple melanoma antigens so that the adjuvant activity of IL-2 + GM-CSF liposomes with different antigens can be evaluated. Successful completion of this work will provide a new method to increase the effectiveness of melanoma vaccines, and may lead to an improved treatment for the primary and secondary prevention of this cancer. More broadly, it may provide a general method of potentiating the immunogenicity of vaccines against other cancers and to infectious diseases.